RT info:eu-repo/semantics/doctoralThesis
T1 Remodeling of G protein coupled receptors signaling pathways in essential hypertension
A1 Daghbouche Rubio, Nuria
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Hipertensión
K1 Essential hypertension
K1 Hipertensión esencial
K1 Ion channels
K1 Canales iónicos
K1 Vascular smooth muscle cells
K1 Células de músculo liso
K1 GPCR
K1 GPCR
K1 2411.03 Fisiología Cardiovascular
AB Hypertension (HT) is the most common modifiable risk factor for cardiovascular disease, Strategies to control HT have a limited success, so there is an unmet need for identification of more efficient treatments for HT. A better understanding of the mechanisms regulating blood pressure, using genetic, molecular and physiological approaches, could identify novel pathways that can be potential drug targets, so that we can treat HT with a mechanistic-driven approach. We have use a mice model of essential HT (BPN, blood pressure normal, and BPH, blood pressure high) to explore the changes in the contractile responses of mesenteric arteries to agonists acting through G protein-coupled receptors (GPCR). Microarrays of vascular smooth muscle cells (VSMCs) from BPN and BPH mice provided differential expression of several elements in GPCR signaling pathways, and some of the most significant changes were functionally investigated. We found an increased expression of the purinergic receptor P2Y6 the, which correlates with augmented UTP-induced contractions in BPH arteries. Moreover, we described here that the upregulation of P2Y6R affects the contractile responses to angiotensin II (AgII), favoring the formation of heterodimers with the AgII receptors ATR1. ATR1 desensitization in the P2Y6R-ATR1 complexes is decreased, and this can contribute to the increased contractile responses to AgII in HT arteries. In spite of this increased response, we found  reduced circulating AgII levels and less hypotensive effect in response to treatment with the ATR1 blocker losartan, indicating that overstimulation of the renin-angiotensin aldosterone system (RAAS) does not contribute to HT in BPH. Our data suggest that P2Y6R levels may represent a molecular switch to induce HT, so that this receptor may become a promising target for the treatment of HT. We also characterize the variations in α-adrenergic signaling pathways in HT. The α1-adrenergic agonist Phenylephrine (Phe) elicited larger contractions in BPH vessels, so we investigated the potential mechanisms involved in this enhanced response. We explored the contribution of Ca2+ release from intracellular stores or the activation of L-type Ca2+ channels (LTCC), Ca2+ activated Cl- channels and the transient receptor potential cation channels (TRPC3/6). Although some of these elements show changes in the BPH vessels, none of them recapitulates the increased contractile response. The contribution of phospholipase C (PLCβ) or rho-associated protein kinase (ROCK) to Phe-induced contraction was also decreased in BPH vessels, suggesting the presence of an additional mechanism activated by Phe and distinct from PLCβ or ROCK signaling pathways in BPH Overall, we found that the increased contractile responses to GPCRs agonist in HT is the result of a complex dysregulation of multiple molecular components rather than caused by changes in single elements. This pattern is in clear agreement with the multifactorial nature of the disease. Another important conclusion derived from the complex nature of this disease is the need to explore the effect of every molecular element in the proper context, considering the likely concomitant changes of its partners in the pathway.
YR 2024
FD 2024
LK https://uvadoc.uva.es/handle/10324/67243
UL https://uvadoc.uva.es/handle/10324/67243
LA eng
NO Escuela de Doctorado
DS UVaDOC
RD 06-ago-2024